Efficient syntheses of isotopically labeled PD0198961, a novel synthetic coagulation factor Xa inhibitor

Article abstract of DOI:10.1002/jlcr.1595

PD0198961 was investigated as a potent and selective inhibitor of coagulation factor Xa for the treatment of thrombotic disorders. Radioactive and stable isotope-labeled PD0198961 were synthesized for absorption, distribution, metabolism and elimination s

Full text of DOI:10.1002/jlcr.1595

Research Article
Received 7 November 2008,
Revised 23 December 2008,
Accepted 31 January 2009
Published online 23 March 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1595
Efficient syntheses of isotopically labeled
PD0198961, a novel synthetic coagulation
factor Xa inhibitor
Ã
Yinsheng Zhang
PD0198961 was investigated as a potent and selective inhibitor of coagulation factor Xa for the treatment of thrombotic
disorders. Radioactive and stable isotope-labeled PD0198961 were synthesized for absorption, distribution, metabolism
and elimination studies of the compound in animals and for use as mass spectral internal standards in support of
bioanalytical assays, respectively. [14C]PD0198961 was prepared from [14C]CuCN in four radiosynthetic steps in an overall
yield of 48% with a radiochemical purity of 499%. The cyanation reaction of an aromatic bromide with inorganic
[
14C]cyanide as a key radiolabeling step was investigated. The deuterium-labeling was accomplished in a different reaction
sequence from the 14C labeling. This convergent process introduced stable isotope labeling via cis-2,6-dimethyl[2H5]piper-
idine, which was synthesized by catalytic hydrogenation of 2,6-dimethylpyridine with deuterium gas.
Keywords: PD0198961; factor Xa; carbon-14 labeling; stable-isotope labeling; cyanation; amidine formation
1,5-dibromopentane in the presence of NaH to provide two
isomers (N-alkylation and O-alkylation products). The desired N-
Introduction
Factor Xa (FXa) has materialized as a key enzyme for the
intervention of the blood coagulation cascade and for the
development of new antithrombotic agents.1 FXa is the lone
enzyme responsible for the production of thrombin and
therefore is an attractive target for the control of thrombus
formation.2 PD0198961 is a novel, potent (Ki = 0.83 nM) and
selective FXa inhibitor used for the treatment of thrombotic
disorders. A radiolabeled analog of PD0198961 was required to
profile and measure the absorption, distribution, metabolism
and elimination of the compound in animals. Stable-isotope
labeled PD0198961 was also required for use as an internal
standard for bioanalytical assay of phase I human clinical sample
quantitative biotransformation studies. This paper focuses on
alkylated compound 11 was isolated by flash column chroma-
tography in 41% yield. Displacement of the alkyl bromide 11
with varying equivalents of 2,6-dimethylpiperidine was studied.
The excess of 2,6-dimethylpiperidine as a reagent and a solvent
was used previously in the original discovery synthesis (Scheme
1); however, it was not necessary to achieve high yields. It was
found that 3 equiv. of 2,6-dimethylpiperidine in DMF was
enough to obtain a good yield.
Cyanation of the aryl bromide 12 was a key radiolabeling
step. The reaction was investigated in various reagents, solvents
and molar ratios. The results were shown in Table 1. Using
reaction conditions with KCN as a cyanation reagent and
Pd(PPh3)4 as a catalyst (entry 1), which were similar to the
2
efficient syntheses of both 14C-labeled and H-labeled analogs
of PD0198961 (Figure 1).
HN
NH2
Results and discussion
N
N
Unlabeled PD0198961 was originally synthesized in ten steps as
shown in Scheme 1.3 The step (5–6) for installing the aryl nitrile
functionality was considered to introduce the 14C radiolabel.
However, the sequence of the original synthesis was not
suitable to prepare radioactive labeled compounds. The major
problems were that more than 50% of radioactivity would be
lost as an O-akylation by-product in the N-alyklation step and a
lot of undesired over-reduced byproducts were formed in the
last hydrogenation reaction with Pd/C. To solve these problems,
a new approach to the synthesis of isotope labeled PD0198961
has been explored (Scheme 2).
OH
O
N
Figure 1. PD0198961.
Radiochemistry Group, Research API, Groton Labs, Pfizer Global R&D, Eastern
Point Rd, Groton, CT 066340, USA
Therefore, our new approach was to prepare the aryl bromide
precursor 12 and then introduce 14C labeled cyano group in the
later step. The available intermediate 5 was first treated with
*Correspondence to: Yinsheng Zhang, Radiochemistry Group, Research API,
Groton Labs, Pfizer Global R&D, Eastern Point Rd, Groton, CT 066340, USA.
E-mail: yinsheng.zhang@pfizer.com
J. Label Compd. Radiopharm 2009, 52 273–277
Copyright r 2009 John Wiley & Sons, Ltd.

Y. Zhang
reported procedure,4
a
poor yield (10%) was observed. hydrogenation reaction of 2,6-dimethylpyridine with D2/PtO2
Application of CuCN in DMF gave a 40% isolated yield of in acetic acid7 and deuterated acetic acid was studied. In acetic
the cyanide 13 within 24 h at 1751C. Increasing the molar acid, the reaction provided a lot of unlabelled 2,6-dimethyl-
ratio of CuCN to the compound 12 from 1.1 to 1.5 improved piperidine (D0) besides deuterium labelled compounds (D1–D5).
the yield to 55% (entry 3), while increasing the temperature While in deuterated acetic acid, the desired product (M15) was
of the cyanation reaction with CuCN from 175 to 2101C a major isotopomer (91% isotopic purity). A small amount of
caused significant decomposition (entry 4). Interestingly, addi- (M14) and (M16) was found, but no (M10) was detected. These
tion of pyridine to the cyanation reaction with CuCN improved results indicated that the exchange occurred between deuter-
the yield from 40 to 70% (entry 5). It was found that a higher ium from D2 gas and hydrogen from acetic acid.
reaction temperature resulted in the more decomposition.
According to our previous study, use of an excess of 2,6-
Therefore, by reducing the temperature to 1601C and increasing dimethylpiperidine as a reagent and solvent was not necessary
the reaction time to 48 h, we were able to obtain better isolated to achieve high yield in next step. Therefore, about 3 equiv. of
yields (entry 6,7).
Previously, PD0198961 was obtained by the treatment of reaction to produce the desired compound 19 in an isolated
cyanide 13 with hydroxylamine5 followed by
catalytic yield of 86%. It was observed that the deuteriums in
[D5]2,6-dimethylpiperidine in DMF was used in the N-alkylation
a
hydrogenation. The uncontrolled over-reduction reaction 2,6-positions of [D5]2,6-dmethylpiperidine could be exchanged
caused poor yields and difficult separations. Therefore, the with protons from reagents (HCl) and solvents (H2O) under
indirect transformations of cyanide to amidine were investi- heating conditions. To avoid losing deuteriums, deuterated
gated. A classic method, i.e. alcoholysis of cyanide 13 in the solvents and reagents were used for the amidine formation
presence of HCl gas followed by amination with NH3 gas, and debenzylation reactions. The nitrile 19 was converted
worked just fine for our case, and provided the desired to the amidine 21 by using Pinner conditions in the presence
amidine 15 in an isolated yield of 61%. An alternative, one of deuterated hydrochloric acid and ethanol followed by
step transformation with methylchloroaluminum amide amination with NH3 gas. Finally, the phenolic benzyl ether
(MeAlClNH2)6 was tried without success. The catalytic hydro- was removed by hydrolysis of the ether 21 in deuterated
genation to remove the protecting group was not applied due HCl and MeOH to afford the desired [D5]PD0198961 in 39%
to the previous unsatisfactory results. Since compound 15 was overall yield.
fairly stable under acid conditions, the debenzylation of amidine
In summary, 14C labeled PD0198961 was synthesized in four
15 by concentrated HCl in MeOH provided the desired product radiosynthetic steps starting from [14C]CuCN. The overall radio-
in an excellent yield (98%) with a radiochemical purity of 499% chemical yield was 48% with a radiochemical purity 499% and a
and a specific activity of 54 mCi/mmol.
specific activity 54.0 mCi/mmol. The study on the cyanation
The synthesis of deuterated PD0198961 (M15) was carried reaction of the aromatic bromide with inorganic [14C]cyanide
out by following the original reaction sequence (Scheme 3), showed that the presence of pyridine in the CuCN cyanation
which enabled us to incorporate the stable isotope labeled reaction improved the yield from 40 to 87%. The deuterium-
intermediate 18 into the target in the later steps. The labeling was accomplished by PtO2-catalyzed hydrogenation of
Br
Br
Br
Br
DMSO/(COCl)2
Et3N/CH2Cl2
-78oC
1) HCl/dioxane
MeOH/Et2O
2) H2O/dioxane
O
KCN, AcOH
MeOH
O
NC
MeO
OHC
MeO
60%
OCH2Ph
O
OCH2Ph
OH OCH2Ph
OH OCH2Ph
1
4
3
2
CN
CN
Br
CuCN
DMF
1,2-phenylenediamine
MeOH/65oC
1,5-dibromopentane
NaH/DMF
N
N
N
58%
49%
OCH2Ph
94%
OCH2Ph
OCH2Ph
N
O
N
H
O
N
O
H
(CH2)5Br
5
6
7
HN
NH2
HN
NHOH
CN
H2NOH-HCl
DIEA
cis-2,6-dimethypiperidine
DMF
1) TFAA
2) H2/Pd/TFA
N
N
N
N
85%
OCH2Ph
OH
30%
OCH2Ph
N
N
O
O
O
(CH2)5
(CH2)5
(CH2)5
N
N
N
10 PD-0198961
8
9
Scheme 1. Original synthesis of unlabeled PD0198961.
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J. Label Compd. Radiopharm 2009, 52 273–277

Y. Zhang
Br
Br
Br
1,5-dibromopentane
NaH/DMF/75oC
cis-2,6-dimethypiperidine
DMF/75oC
N
N
[
14C]CuCN
N
N
DMF/Py/160oC
N
OCH2Ph
41%
O
OCH2Ph
80%
OCH2Ph
82%
O
N
H
O
(CH2)5Br
(CH2)5
N
5
11
12
*
CN
HN
NH2
*
HN
OEt
*
HCl
N
1) HCl/MeOH
72oC
N
N
N
N
NH3/MeOH
EtOH/HCl
OCH2Ph
5-25oC
0oC
N
O
OCH2Ph
OCH2Ph
2) NH4OH
98%
O
O
61%
(CH2)5
N
(CH2)5
(CH2)5
N
N
13
14
15
HN
NH2
*
N
N
OH
O
(CH2)5
N
16 [14C]PD0198961
Scheme 2. Synthesis of [14C] PD0198961.
Table 1. The cyanation of bromide 13
Br
*
CN
N
See Table 1
N
N
OCH2Ph
N
O
OCH2Ph
O
N
N
12
13
Entry
Condition
Molar ratio of 12/MCN
Yield (%)
1
2
3
4
5
6
7
KCN/Pd(PPh3)4 18-crown-6/THF-EtOH/851C/24 h
CuCN/DMF/1751C/24 h
CuCN/DMF/1751/24 h
1:1.2
1:1.1
1:1.5
1:1.1
1:1.1
1:1.1
1:1.1
10
40
55
20
70
87
82
CuCN/NMP/2101/24 h
CuCN/DMF/Py/1751C/24 h
CuCN/DMF/Py/1601C/48 h
[14C]CuCN/DMF/Py/1601C/48 h
2,6-dimethylpyridine to cis-2,6-dimethyl[2H5]piperidine, which
was subsequently incorporated into the target molecule
with excellent chemical purity (99.6%) and high isotopic enrich-
ment (91% D5).
Experimental
All reactions were carried out under an atmosphere of nitrogen
unless otherwise stated. 1H and 13C NMR spectra were recorded
J. Label Compd. Radiopharm 2009, 52 273–277
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

Y. Zhang
HN
OEt
HCl
CN
H
N
1)D2/CD3COOD
PtO2
7 /DMF/75oC
N
N
N
EtOD/DCl
0oC
N
N
86%
2)Na2CO3/D2O
68%
OCH2Ph
OCH2Ph
O
D5
O
(CH2)5
N
(CH2)5
N
17
18
D5
D5
19
20
HN
NH2
HN
NH2
N
N
1) DCl/MeOD/72oC
N
N
NH3/MeOH
0-25oC
68%
OCH2Ph
OH
O
2) NH4OH
98%
O
(CH2)5
N
(CH2)5
N
D5
D5
21
22 [D5]PD0198961
Scheme 3. Synthesis of [D5]PD0198961.
on a Varian Gemini 200 or 400 MHz instrument. Chemical purity and poured into water (200 ml). The aqueous layer was
of all labeled compounds was determined by HPLC and GC-MS extracted with EtOAc (50 ml  3). The combined organic layers
or LC-MS. Purifications were done by flash column chromato- were washed with brine (50 ml  10), and dried over MgSO4. The
graphy on Biotage Flash 40 system. [14C]KCN (250 mCi, solvent was evaporated to give an oily residue, which was
54 mCi/mmol) was purchased from American Radiolabeled Che- applied to flash chromatography. The pure titled compound 12
micals, Inc. The intermediates 5 and 7 were provided by Chemical was obtained as a colorless oil (2.68 g, 81%). 1H NMR (CDCl3) 7.90
R&D, Ann Arbor Lab, Pfizer Inc. All prepared stable-isotope labeled (d, 1H), 7.60–7.43 (m, 2H), 7.44–7.21 (m, 8H), 6.88 (d, 2H), 5.07 (s,
compounds contained less than 0.01% of unlabeled material based 2H), 4.23 (t, 2H), 2.77 (t, 2h), 2.35–2.48 (m, 2H), 1.80–1.21(m, 12H),
on LC-MS analysis; otherwise as indicated.
1.10 (d, 6H), 1.0–1.20 (m, 2H). 13C NMR (CDCl3) 156.89, 156.133,
3-(2-(Benzyloxy)-5-bromophenyl)-1-(5-bromopentyl)quinoxalin- 154.16, 137.14, 133.89, 133.61, 133.35, 131.18, 131.10, 129.38,
2(1H)-one (11): To a solution of aryl bromide 5 (8.16 g, 128.83, 128.22, 127.65, 123.94, 115.16, 114.09, 113.78, 71.44,
20.0 mmol) in DMF (120 ml) was added NaH (60%, 2.40 g, 56.06, 53.16, 48.48, 42.97, 35.39, 34.02, 27.73, 25.56, 25.12, 23.45,
60.0 mmol) at 01C. The resulting suspension was stirred at room 23.07, 21.71; MS (CI) m/z 587, 589.
temperature for 45 min. To the reaction mixture was then added
4-(Benzyloxy)-3-(4-(5-cis-2,6-dimethylpiperidin-1-yl)pentyl)-3-oxo-
1,5-dibromopentane (16.0 ml, 117.7 mmol) at room temperature. 3,4-dihydroquinoxalin-2-yl-[14C]benzonitrile (13): To a mixture of
The mixture was stirred at room temperature for 18 h, and then [14C]CuCN (93.6 mCi, 1.73 mmol, 54 mCi/mmol) in pyridine
poured into water (300 ml). The aqueous layer was extracted (0.4 ml) and DMF (15 ml) was added the aryl bromide 12
with EtOAc (35 ml  3). The combined organic layers were (0.97 g, 1.65 mmol). The reaction mixture was stirred at room
washed with brine (25 ml  2) and dried over MgSO4. The temperature for 20 min, and then at 1601C for 48 h. The
solvent was evaporated to give a colorless oil, which was precipitates were filtered off. The filtrate was poured into water
applied to flash silica gel chromatography (6/1 hexane/EtOAc). (80 ml), and extracted with EtOAc (25 ml  4). The combined
The titled compound 11 was obtained as colorless oil (4.55 g, organic layers were washed with 10% NH4OH (15 ml  2), water
41%). 1H NMR (CDCl3) 7.93 (dd, 1H), 7.62–7.49 (m, 2H), 7.39–7.26 (15 ml  2) and brine (15 ml  2), and dried over MgSO4. The
(m, 8H), 6.92 (d, 1H), 5.10 (s, 2H), 4.26 (t, 2H), 3.39 (t, 2H), concentration of the organic layer provided brown oily residue,
1.95–1.57 (M, 6H); 13C NMR (CDCl3) 156.89, 156.185, 154.18, which was applied to flash chromatography (20/1/0.1 CH3Cl/
137.15, 133.96, 133.63, 133.35, 133.29, 131.27, 131.15, 129.34, MeOH/NH4OH). The title compound 13 was prepared as a
128.86, 128.27, 127.67, 124.04, 115.17, 114.00, 113.85, 71.46, yellowish oil (0.871 g, 82%, radiochemical purity 98.4%, 54 mCi/
1
42.65, 33.82, 32.69, 26.85, 25.99; MS (Cl) m/z 554, 556; The mmol, 87.8 mCi). H NMR (DMSO-d6) 7.95 (dd, 1H), 7.93 (d, 1H),
O-alylation by-product was also isolated as a colorless oil 7.86 (d, 1H), 7.6–7.7 (m, 2H), 7.2–7.4 (m, 7H); 5.22 (s, 2H), 4.23 (t,
(0.556 g, 50%). 13C NMR 156.50, 156.39, 140.97, 139.04, 136.98, 2H), 0.9–2.5 (m, 22H); MS (CI) m/z 535, 557.
133.81, 133.72, 133.60, 130.43, 129.50, 129.18, 128.93, 128.23,
4-(Benzyloxy)-3-(4-(5-((2R,6S)-2,6-dimethylpiperidin-1-yl)pentyl)-
127.355, 127.08, 126.94, 114.78, 113.73, 70.94, 66.82, 34.15, 3-oxo-3,4-dihydroquinoxalin-2-yl)[14C]benzamidine (15): Dry HCl gas
32.73, 28.23, 25.20; MS (CI) m/z 554, 556
3-(2-(Benzyloxy)-5-bromophenyl)-1-(5-(cis-2,6-dimethylpiperidin-
was introduced to a reaction mixture of compound 13 (0.81 g,
81.5 mCi, 1.51 mmol) in dry EtOH (25 ml) at 01C for 3.5 h. The
1-yl)pentyl)quinoxalin-2(1H)-one (12): To a solution of dibromide reaction mixture was warmed up slowly to room temperature.
11 (3.136 g, 5.65 mmol) in DMF (15 ml) was added cis-2,6- The solvent was removed under reduced pressure to give ethyl
dimethylpiperidine (22.8 ml, 16.95 mmol). The solution was imidate ether 14. The crude compound 14 was dissolved in dry
stirred at 751C for 18 h, and then cooled to room temperature MeOH (16 ml). Dry NH3 gas was introduced to the reaction
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J. Label Compd. Radiopharm 2009, 52 273–277

Y. Zhang
solution at 51C for 3.5 h. The mixture was stirred at room (m, 6H), 1.08(s, 6H). 13C NMR (CDCl3) 160.91, 155.35, 154.05,
temperature for 15 h. The concentration of the mixture gave 136.25, 135.65, 134.89, 133.60, 133.42, 131.45, 131.31, 128.99,
crude yellow oil, which was applied to flash column chromato- 128.68, 128.56, 127.65, 124.15, 119.22, 114.19, 113.62, 105.04,
graphy. The title compound 15 was obtained as a white solid 71.38, 48.46, 43.08, 35.50 (m), 27.76, 25.60, 23.65, 21.77, 21.63;
(0.509 g, 49.8 mCi, 61%). 1HNMR (DMSO-d6) 8.65 (bs, 4H), 7.50 MS (CI) m/z 539.
(dd, 1H), 7.90 (d, 1H), 7.85 (d, 1H), 7.66 (d, 2H), 7.42–7.24 (m, 7H),
5.23 (s, 2H), 4.24 (t, 2H), 2.65–2.43 (m, 2H), 2.31–2.1.5 (m, 2H); 13
4-(Benzyloxy)-3-(4-(5-cis-2,6-dimethyl[D5]piperidin-1-yl)pentyl)-3-
oxo-3,4-dihydroquinoxalin-2-yl-benzonitrile (21): The same proce-
C
NMR (DMSO-d6) 163.33, 156.30, 154.41, 137.84, 134.29, 134.19, dure as for the preparation of compound 15 was followed. From
133.01, 132.72, 131.51, 131.55, 129.86, 129.45, 129.37, 128.65, compound 19 (0.733 g) the title compound 21 was obtained as
1
125.61, 121.56, 116.19, 114.76, 72.26, 60.26, 60.58, 43.33, 33.69, a white solid (0.514 g, 68%). H NMR (CD3OD) 8.0–7.87 (m, 3H),
28.18, 24.95, 23.74, 18.89, 18.80; MS (CI) m/z 551, 553.
7.72–7.60 (m, 2H), 7.48–7.25 (m, 7H), 5.25 (s, 2H), 4.34 (t, 2H), 2.80
3-(4-(5-(Cis-2, 6-dimethylpiperidin-1-yl)pentyl)-3-oxo-3, 4 - dihydroqui- (t, 2H), 1.78–1.65 (m, 2H), 1.58–1.29 (m, 7H), 1.12 (s, 6H); 13C NMR
noxalin-2-yl)-4-hydroxy[1-14C]benzamidine (16, [14C]PF0198961): A (CD3OD) 167.58, 163.30, 156.49, 155.75, 137.81, 134.71, 134.22,
mixture of compound 15 (0.213 g, 20.8 mCi, 0.385 mmol) in MeOH 132.95, 132.67, 131.50, 129.83, 129.41, 129.32, 128.71, 125.56,
(6 ml) and concentrated HCl solution (3.5 ml) was stirred at 721C for 121.70, 116.11, 114.67, 72.28, 57.37, 43.72, 34.68 (m), 28.56,
24 h. The solvent was evaporated under reduced pressure to give 25.84, 23.02, 20.77, 20.61; MS (CI) m/z 556.
the crude product 16 as a yellow oil, which was applied to flash
3-(4-(5-(Cis-2,6-dimethyl[D5]piperidin-1-yl)pentyl)-3-oxo-3,4-dihy-
column chromatography (alumina, CH3CN/H2O/NH4OH = 100/5/1). droquinoxalin-2-yl)-4-hydroxybenzamidine (22, [D5]PF0198961):
The title compound [14C]PD0198961 was obtained as a yellow solid The same procedure as for the preparation of compound 16 was
1
(0.176 g, 20.5 mCi, 98%). HNMR (CD3OD) 9.31 (d, 1H), 7.96 (d, 1H), followed. From compound 21 (0.501 g) the title compound 22
7.85 (dd, 1H), 7.81–7.74 (m, 2H), 7.55–7.51 (m, 2H), 7.20, (d, 1H), 4.51 was obtained as a bright yellow solid (0.41 g, 98%). 1H NMR
(t, 2H), 3.1–3.4 (m, 2H), 2.0–1.3 (m, 20H); 13C NMR (CD3OD) 163.30, (CD3OD) 11.95 (bs), 10.65 (bs), 9.30 (s, 1H), 9.17 (s, 1H), 8.27–7.15
156.28, 154.40, 137.81, 134.26, 134.17, 133.0, 132.70, 131.48, 131.52, (m, 5H), 4.27 (m, 2H), 3.91 (m, 4H), 3.09 (m, 3H), 1.85–1.42
129.84, 129.44, 129.36, 128.64, 125.62, 60.25, 60.59, 43.33, 33.68, (m, 6H), 1.02 (s, 6H); 13C NMR (CD3OD) 167.55, 163.28, 156.45,
28.16, 24.93, 23.73, 18.85, 18.79; MS (CI) m/z 462, 464. Radiochemical 155.73, 137.80, 134. 69, 134.20, 132.90, 132.68, 131.48, 129.80,
purity: 99.1%; chemical purity: 99.6%; HPLC conditions: column: 129.42, 129.31, 128.68, 125.54, 57.35, 43.70, 34.67 (m), 28.55,
Hypersil BDS C18, 5 um, 4.6 Â 250 mm; mobile phase: A=0.1% THF 25.83, 23.00, 20.77, 20.59; MS (CI) m/z 466 (91% isotopic purity);
in H2O, B= 0.1% THF in CH3CN, initial to 5 min, A:B= 75:25, chemical purity (CP) 99.60%, HPLC conditions: column: Hypersil
5–10 min, A:B= gradient to 50:50, hold A:B= 50:50 to 30 min; flow BDS C18, 5 um, 4.6 Â 250 mm; mobile phase: A = 0.1% THF in
rate: 1.0 ml/min; UV detection: 225 nm; retention time: 11.3 min. H2O, B = 0.1% THF in CH3CN, initial to 5 min, A:B = 75:25,
Specific activity: 54 mCi/mmol.
5–10 min, A:B = gradient to 50:50, hold A:B 50:50 to 30 min; flow
2,6-Cis-[D5]dimethylpiperidine (18): A mixture of 2,6-dimethyl- rate: 1.0 ml/min; UV detection: 225 nm; retention time: 11.3 min.
pyridine (10 g, 93.5 mmol) in CD3COOD (20 ml) was hydroge-
nated with D2 gas under 50 psi in the presence of PtO2 (1 g). The
catalyst was filtered off, and the filtrate was evaporated to
dryness under reduced pressure. The residue was dissolved in
Acknowledgement
CH2Cl2 (30 ml). To this solution was added Na2CO3 (15 g). The
suspension was stirred at room temperature for 2 h and filtered
to give a colorless liquid. The distillation of the crude material
The author thanks Drs C. C. Huang and Om P. Goel for helpful
discussions and valuable remarks concerning this work, and Dr
Zhijian Zhu for kindly providing the unlabeled intermediates.
1
gave the titled compound 18 as a colorless oil (7.4 g, 68%). H
NMR (CDCl3) 1.6–1.4 (m, 2H), 1.3–1.1 (m, 1H), 0.98 (s, 6H); MS (CI)
m/z 117, 118 (90%), 119
4-(Benzyloxy)-3-(4-(5-cis-2,6-[D5]dimethylpiperidin-1-yl)pentyl)-
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bromide 7 (0.812 g, 1.62 mmol) and compound 18 (0.60 g,
5 mmol) in DMF (2.0 ml) was stirred at 701C for 24 h. The reaction
mixture was poured into D2O (15 ml), and extracted with EtOAc
(20 ml  3). The combined organic layers were washed with
brine (6 ml  2), and dried over MgSO4. The solution was
evaporated to give the crude product 19 as a yellow oil, which
was applied to flash column chromatography (silica, CH3Cl/
MeOH/NH4OH: 20/1/0.1). The title compound 19 was obtained
1
as a colorless oil (0.751 g, 86%). H NMR (CDCl3) 7.93 (dd, 1H),
7.76 (dd, 1H), 7.67–7.57 (m, 1H), 7.42–7.26 (m, 8H), 7.06 (d, 1H),
5.17 (s, 2H), 4.26 (t, 2H), 2.73 (t, 2H), 1.80–1.70 (m, 3H), 1.56–1.15
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J. Label Compd. Radiopharm 2009, 52 273–277
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